In the body, tissue homeostasis is established and maintained by resident tissue-specific adult stem cells (aSCs). Through preservation of bidirectional communications with the surrounding niche and integration of biophysical and biochemical cues, aSCs actively direct the regeneration of aged, injured and diseased tissues. Currently, the ability to guide the behavior and fate of aSCs in the body or in culture after prospective isolation is hindered by our poor comprehension of niche composition and the regulation it imposes. Two-and three-dimensional biomaterials approaches permit systematic analysis of putative niche elements as well as screening approaches to identify novel regulatory mechanisms governing stem cell fate. The marriage of stem cell biology with creative bioengineering technology has the potential to expand our basic understanding of stem cell regulation imposed by the niche and to develop novel regenerative medicine applications.